A wide variety of 5-acyl-1-hydrocarbylpyrrole-2-acetic acid are known to possess useful pharmacological properties. For example, 1-methyl-5-p-toluoylpyrrole-2-acetic acid has a marked anti-inflammatory activity [J. Pharmacology and Experimental Therapeutics, 185, 127 (1973)]. See also U.S. Pat. Nos. 3,752,826; 3,775,307; 3,803,169; 3,803,171 and 4,048,191 which describe, inter alia, numerous 5-acyl-1-hydrocarbylpyrrole-2-acetic acids having anti-inflammatory and analgetic activities.
In co-pending Application Ser. No. 963,673, filed Nov. 27, 1978 (the disclosure of which is incorporated herein), now U.S. Pat. No. 4,238,396, Kondo, Suda and Tunomoto describe a novel and useful three step synthesis for producing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid, the first step of which involves the preparation of 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol.
Although it is known that 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol can be formed by reaction of chloral with N-hydrocarbylpyrrole, this process has not been without shortcomings and limitations. About a quarter of a century ago, R. C. Blinn et al. reported in J. Am. Chem. Soc., 76, 37-39, (1954), the synthesis of 2,2,2-trichloro-1-(N-methylpyrryl-2)-ethanol by addition of 0.2 mol of freshly distilled chloral to a solution of 0.4 mol of N-methylpyrrole in 300 ml diethyl ether at 0.degree. C. followed by addition, with cooling, of 0.2 mol of anhydrous zine chloride in 700 ml of anhydrous ether at a rate to maintain the temperature at below 0.degree. C. The product was produced in 26.5 percent yield. The authors indicated that the use of the molecular quantities of anhydrous zinc chloride and the use of the low reaction temperatures were necessary in order to cope with the instability of the resultant 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol adduct. Because of its low yields, its use of a dilute reaction system, excess N-methylpyrrole and large amounts of zinc chloride, and its need for low temperature control, this process is not suitable or practical for commercial usage.
As a result of their studies on the process, Kondo, Suda and Tunemoto found that it was possible to obtain the 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol adduct in almost quantitative yield by reacting chloral with N-hydrocarbylpyrrole at from -10.degree. C. to about 36.degree. C. without using a Lewis acid catalyst such as zinc chloride. As reported in their above refered to co-pending application, it was discovered that the rate of this reaction-which is preferably conducted in the presence of solvents which do not directly affect on the reaction, for example, ethereal solvents such as diethyl ether, dioxane, THF, and the like, and hydrocarbons such as benzene, toluene, hexane, and the like--is dependent on the origin (or the purity) of chloral used. Chloral from a freshly opened bottle did not react with N-methylpyrrole at room temperature and only after prolonged reflux (sometimes several days) was the adduct formed. In contrast, chloral from an old bottle reacted instantly at room temperature. Acting on the hypothesis that trichloroacetic acid, which is formed easily by the oxidation of chloral, does catalyze this reaction, they found that the addition of organic acid such as trichloroacetic acid, acetic acid or p-toluene-sulfonic acid to the reaction mixture accelerates this reaction. They further report that among these three acids p-toluene-sulfonic acid appears more effective than the others and that in carrying out the process in the presence of a protonic acid added preferably in the form of an organic acid or a cation exchange resin, the adduct (i.e., the 2,2,2-trichloro-(N-hydrocarbylpyrryl-2)-ethanol) has been readily formed in almost quantitative yield.
While the foregoing process represents a distinct advance in the art, some difficulties still remain. In order to achieve high yields, relatively long reaction periods have been used. For instance, in their Example 2 wherein the adduct was formed using p-toluenesulfonic acid, the reactants were refluxed in ether for 15 hours. Further, in order to protect the adduct against premature decomposition, hydroquinone was introduced into the reaction mixture. While this process can be carried out reasonably well in higher boiling ethers such as dioxane, this causes complications in ensuing product separations used in the three step Kondo et al. process for producing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid.